This proposal is for a career development award to prepare the candidate as an independent investigator in the area of the biological determinants of addiction and individual susceptibility to drug abuse, particularly endocrinological factors involved in stimulant response. The K08 award will provide financial support for human laboratory studies of drug response in the presence of manipulation of cortisol levels. Preclinical studies have linked corticosteroids and animal modes of drug addiction. The proposed experiments will provide a better understanding of the contribution of cortisol to methamphetamine addiction in human drug users. The principal mentor will be Dr. Reese Jones in whose Drug Dependence Research Center (DDRC) at Langley Porter Psychiatric Institute (LPPI) studies of human drug response, including methamphetamine studies, have been conducted for several decades. Dr. John Mendelson at the DDRC will serve as a co-mentor. For developing expertise in the area of psychoendocrinology, Dr. Victor Reus and Dr. Owen Wolkowitz, also at LPPI, will serve as co-mentors. Their expertise in the psychiatric effects of corticosteroid modulating agents will provide guidance in this area. During this period the candidate will learn methodologies in pharmacokinetic and pharmacodynamic assessment, corticosteroid manipulation, and assessment of steroid and stimulant response. Subjects will be methamphetamine users experienced in the use of the drug, without a history of serious adverse effects, and familiar with effects of the drugs. Experienced users would likely represent sensitized users, making it possible to study the role of corticosteroids in the maintenance of addiction, relevant to the target population of dependent users. Subjective, physiological, and endocrine responses to augmenting cortisol level with hydrocortisone and to lowering cortisol level with the corticosteroid synthesis inhibitor metyrapone will be studied. If lowering cortisol levels reduces the reinforcing effects of methamphetamine, antiglucocorticoid treatment could prove to be an important component of stimulant abuse treatment.